Aim of this study was to assess the structural, ultrastructural, immunohistochemical, and clinical aspects in Sprague-Dawley rats with dextrane sulfate sodium (DSS)-induced colitis. Colitis was induced in Sprague-Dawley rats by seven days of DSS oral administration followed by seven days of tap water only (for one, two and three cycles). Controls were fed with water only. Segments of proximal, mid-, and distal colon of each animal were adequately prepared for light and scanning electron microscope observations. The severity of the lesions was scored histologically. For immunohistochemical study, a cocktail of S-100, NSE, and antineurofilament antibodies was used. Symptoms such as weight, feces consistency, diarrhea, hematochezia were recorded daily. From a clinical point of view symptoms appeared significantly later after the first cycle than after the second and third cycles and lasted significantly longer in the second and third cycles. Treated rats showed a slower weight gain rate by 20% compared to controls, and the whole colon length appeared to be significantly shorter after colitis induction compared to controls. Structural observations by light microscopy showed prominent involvement of the distal colon. Immunohistochemical study of both submucosal and myoenteric nerve plexuses was similar to controls. Scanning electron microscope observations of the colonic mucosal surface in colitis rats showed a complete subversion of its architecture, characterized by dilatations of gland crypt openings, dropout of goblet cells, and inhomogeneous distribution or lack of microvilli. These were most evident after the third cycle. In conclusion, experimental DSS colitis in SD rats appeared to be highly reproducible and shared most features with human UC, not only from a structural and clinical but also from an ultrastructural point of view.